Colon Cancer is a leading cause of death in the United States. Accordingly, methods of preventing this disease or discovery of agents that increase effectiveness of existing chemotherapeutic agents would be very beneficial. Our studies and those of others have indicated that dietary curcumin, an active ingredient in the spice turmeric, potently inhibits intestinal tumorigenesis. We have now characterized the mechanisms by which curcumin modulates this function. Proliferation, angiogenesis and tumor invasiveness constitute the major pathways that are necessary for the growth and metastatic potential of cancer. Our preliminary studies show that curcumin inhibits cell proliferation, and tumor angiogenesis and invasiveness, while it enhances spontaneous and chemotherapy-induced apoptosis of tumor cells. The goals of the current project are to determine the mechanistic effects of curcumin on each of theses processes. Specifically, we will determine the effects of curcumin on growth factor-mediated activation of cellular signaling pathways. We will also determine the role of curcumin in signaling mediated by epidermal growth factor and prostaglandins, two molecules that are active in cancer progression. In addition, we will determine the effect of curcumin on the expression and regulation of tumor suppressor protein p53, an important regulator of cell survival. We will examine the effect of curcumin on expression of p53 target genes such as p21 WAF1, BAX. Moreover, we will examine the role of curcumin in the expression of VEGF and related angiogenesis factors as well as matrix metalloproteinases as regulators of tumor invasiveness. We will compare the results obtained in cell culture studies with that observed in mice with defined genetic manipulations. Together these studies should provide insight into the cancer process and how curcumin suppresses the risk and proliferation of colon cancer, and of no less importance, why curcumin is of great value as a food supplement. [unreadable] [unreadable]